Expression data from WT and Klrc1-/- CD8+ T cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE74780 | GEO | 2015/11/07
SECONDARY ACCESSION(S): PRJNA301465
REPOSITORIES: GEO
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Project description:CD8+ T cells and NK cells protect from viral infections by killing virally-infected cells and secreting interferon-g. Several inhibitory receptors limit the magnitude and duration of these anti-viral responses. We used microarrays to assess the transcriptome of ectromelia virus (ECTV) specific CD8+ T cells that genetically lack one such receptor, NKG2A, which is encoded by Klrc1. Naïve or ECTV-specific CD8+ T cells were sorted directly into RLT buffer. RNA was then extracted, processed, and hybridized to Affymetrix arrays.
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Project description:Checkpoint blockage has revolutionized cancer treatment. NKG2A is an inhibitory receptor expressed by cytotoxic lymphocytes, including NK cells. In contrast to other checkpoint inhibitory antibodies, anti-NKG2A antibodies have shown only limited success. Here, we designed a Cas9-based strategy to delete KLRC1 from human NK cells. Electroporation of KLRC1-targeting Cas9-RNP efficiently eliminated NKG2A expression from primary human NK cells. NKG2A-deficient NK cells showed normal proliferation, only minor transcriptional changes related to enhanced NK cell activation and maintained their phenotype and licensing status. Genetic deletion of NKG2A fully bypassed HLA-E inhibition and further enhanced NK cell activity against various tumor cell lines, thereby outperforming anti-NKG2A antibodies. In combination with antibody-coating of tumor cells to induce antibody-dependent cellular cytotoxicity, genetic deletion of NKG2A independently promoted cytotoxicity. Thus, Cas9-mediated targeting of NKG2A is an effective way to target this important inhibitory checkpoint. This technique is easily amenable to adoptive cell therapy in the clinical setting, where NKG2A deletion will promote anti-tumor responses and may help NK cells to better infiltrate and persist in an inhibitory tumor microenvironment.
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Project description:Inflammatory monocytes (iMO) and B-cells are the main targets of the poxvirus ectromelia virus (ECTV) in the lymph nodes of mice and play distinct roles in surviving the infection. Infected and bystander iMO control ECTV’s systemic spread, preventing early death, while B-cells make antibodies that eliminate ECTV. Our work demonstrates that within an infected animal that survives ECTV infection, intrinsic and bystander infection of iMO and B-cells differentially control the transcription of genes important for immune cell function and, perhaps, cell identity. Bystander cells upregulate metabolism, antigen presentation, and interferon-stimulated genes. Infected cells downregulate many cell-type-specific genes and upregulate transcripts typical of non-immune cells. Bys and Inf iMO non-redundantly contribute to the cytokine milieu and the interferon response. Furthermore, we uncovered how IFN-I or IFN-γ signaling differentially regulates immune pathways in Inf and Bys iMO and, that at steady state, IFN-I primes iMO for rapid IFN-I production and antigen presentation.
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